FATS7. A strategy for the use of cholesterol lowering drugs in Newcastle, North Tyneside and Northumberland

Agenda item 5.1 MGUG 28/1/15 FATS7 A strategy for the use of cholesterol lowering drugs in Newcastle, North Tyneside and Northumberland A summary of the evidence used to develop FATS7 from FATS6 The recommendations are presented in summary form as a quick reference guide on the first page after the index FATS Steering Group December 2014 1

Agenda item 5.1 MGUG 28/1/15 INDEX SUMMARY of FATS7 (quick reference guide) 3 INTRODUCTION 4 SUPPORTING NOTES 5 Additional notes 9 APPENDICES 13 Appendix 1: Drug costs 13 Appendix 2: People with possible or definite familial hypercholesterolaemia (FH); supplementary guidance to FATS 14 Appendix 3: Additional guidance for assessment and management of statin intolerance 25 Appendix 4: Membership of the group/conflicts of interest 30 Page 2

FATS7 : 2014 This is a lipid lowering drug strategy. It should be used as part of an overall management plan, discussed and agreed with the patient. It is assumed that people with contraindications / drug interactions will be identified and excluded (refer to the BNF/SPCs). This summary should be used with the supporting notes / appendices All people being considered for statin treatment (for doses see below) Measure lipid profile (total cholesterol, HDL cholesterol, non-hdl cholesterol, triglycerides). Fasting is not required. Measure ALT. Measure CK if unexplained muscle pain. If ALT < 3 x normal, CK normal (if measured) prescribe statin Routine monitoring in all patients (primary and secondary prevention) Measure total cholesterol, HDL-C and non-hdl cholesterol at 3 and 12 months, then annually, ALT after 3 months and 12 months. If non-hdl cholesterol reduction < 40%, discuss treatment concordance, lifestyle measures, consider increasing dose of atorvastatin if not maximal. Ensure annual review People with symptomatic or prior occlusive vascular disease Drug flow: start Atorvastatin 80 mg od, but: Reconsider choice and or statin dose if there are drug interactions / intolerances / CKD / increased risk of adverse effects see extra notes Primary prevention in groups not requiring 10 year cvd risk assessment Type 1 diabetes: all adults ( 18 years) should be considered for statin treatment and in particular, target those with: Microalbuminuria/proteinuria Aged > 40 years Had diabetes for > 10 years Established nephropathy Other cardiovascular risk factors (use clinical judgement) CKD (see NICE / local CKD guideline for diagnosis): offer statin treatment for primary and secondary prevention Drug flow: Atorvastatin 20 mg od (discuss with specialist if egfr < 30 ml/min/1.73m 2 ) if no interactions/intolerances/increased risk of adverse effects, and titrate as appropriate Familial hypercholesterolaemia: see appendix 2 Primary prevention in all others (no occlusive vascular disease, Type 1 diabetes, or CKD) Type 2 diabetes Assess 10 year cardiovascular risk using QRISK2 Offer statin treatment if 10 year cardiovascular risk 10% Ensure lifestyle measures are optimised Primary prevention (no diabetes, CKD or occlusive vascular disease) Assess 10 year cardiovascular disease risk using QRISK2 Undertake a full clinical assessment and support lifestyle modification Discuss and agree about statin treatment if 10 year cardiovascular risk 10% and lifestyle modifications are ineffective or inappropriate Additional risk factors Consider additional risk factors when considering drug treatment, together with the QRISK2 risk score, when estimating 10 year CVD risk, notably people: Treated for HIV With severe mental illness Taking medicines that can cause dyslipidaemia (eg antipsychotics, corticosteroids, immunosuppressants) With systemic autoimmune disorders or other systemic inflammatory conditions (eg SLE) With impaired fasting hyperglycaemia Who have made recent changes eg quit smoking, treated BP, lipids etc Drug flow Start Atorvastatin 20 mg od (discuss with specialist if egfr < 30 ml/min/1.73m 2 ), if no interactions/intolerances/increased risk of adverse effects, and titrate as appropriate Additional notes (see full supporting notes / appendices): 1. People intolerant of recommended statin see appendix 3 2. Consider FH if TC > 7.5 mmol/l - see appendix 2. Do not use QRISK2 3. If triglycerides > 4.5 mmol/l: see notes 4. Consider secondary causes of hyperlipidaemia alcohol / thyroid / diabetes / nephrotic syndrome / liver disease / drug induced 5. If ALT raised at baseline, refer to local LFT guidelines. 6. Patients already treated with statins review percent reduction in non-hdl cholesterol from baseline, consider switching to / uptitrating atorvastatin 7. Treatment in general frailty and older people; see supporting notes FATS7 developed in the light of monitoring of FATS1, 2, 3, 4, 5 & 6 Agreed with Primary and Secondary Care Users North of Tyne, incorporating the NICE Lipid modification GL

INTRODUCTION FATS6 has been reviewed to develop FATS7 following publication of the updated NICE lipid modification guideline. The underpinning principles remain the same in that FATS7 is evidence based, whilst also taking into consideration the need for implementation and cost. This is not intended to duplicate the NICE lipid modification guideline (CG181) 1, but rather to summarise and obtain a shared understanding between clinicians locally to support implementation. Clinicians are also encouraged to read the NICE guideline. FATS is a drug treatment strategy and should only be implemented within an overall management plan which has been discussed and agreed with the patient. FATS advice is based on risk not cholesterol, discuss risk not just cholesterol During the discussion about FATS7 the importance of a meaningful discussion between the clinician and the patient when considering management of cardiovascular risk, including the benefits and risks of starting and or up-titrating statin treatment, was emphasised. This was considered to be an important part of the implementation, but extended beyond discussion about statins, and the details about this are not part of the scope of this guideline. The NICE guideline recommends atorvastatin as the first line statin, not simvastatin. Comparative costs of these and other statins are included in appendix 1. The previous supplementary guidance to aid in the identification of patients with possible familial lipid disorders has also been updated, and is included in appendix 2. More detailed recommendations for the recognition and management of statin intolerance have also been developed, and are included in appendix 3. Appendix 3 also includes details of average LDL cholesterol lowering with different intensity statins. FATS7 is intended for all clinicians in the Newcastle, North Tyneside, Northumberland areas involved in treating people for primary and secondary prevention of cardiovascular disease, including coronary disease, cerebro-vascular disease and peripheral arterial disease, and implemented as part of a wider management plan. A summary of the recommendations that can be printed is included at the beginning. This can be laminated if that is required (folded as a double sided A5 or as a single sided A4 sheet). The supporting notes provide additional information. 1 http://www.nice.org.uk/guidance/cg181

SUPPORTING NOTES This is a lipid lowering drug strategy. It should be used as part of an overall management plan which is discussed and agreed with the patient. All patients should have the opportunity for an assessment and informed discussion about management of their cardiovascular risk, with a healthcare professional with the appropriate skills and knowledge to do that. Details of that are beyond the scope of this guideline, and clinicians should refer to the NICE lipid modification guideline and other local guidance. It is assumed that people with contraindications / drug interactions will be identified and excluded (refer to the BNF/SPCs). Statins and fibrates are contra-indicated in pregnancy. In all women in whom pregnancy is possible, the following should be specifically clarified before starting treatment; whether pregnant, contraceptive status and future pregnancy plans or possibility of pregnancy. Reference should be made to the BNF and relevant SPCs, and the MHRA have previously published recommendations for interactions with simvastatin 2 (see table on page 11) The SPC for atorvastatin (available at http://www.medicines.org.uk/emc/medicine/1424) states that concomitant treatment with medicinal products that are inhibitors of CYP3A4 or transport proteins may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy. Potent CYP3A4 inhibitors include ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors. If co-administration of these medicinal products with atorvastatin cannot be avoided lower starting and maximum doses of atorvastatin should be considered as recommended in the SPC, with appropriate clinical monitoring. Moderate CYP3A4 inhibitors include erythromycin, diltiazem, verapamil and fluconazole and may increase plasma concentrations of atorvastatin and a lower maximum dose of atorvastatin should be considered eg atorvastatin 40 mg daily, with appropriate clinical monitoring. All people being considered for statin treatment (for doses see below) Measure lipid profile (total cholesterol, HDL cholesterol, non-hdl cholesterol, triglycerides). Fasting is not required. Measure ALT. Measure CK if unexplained muscle pain. If ALT < 3 x normal, CK normal (if measured) prescribe statin Routine monitoring in all patients (primary and secondary prevention) Measure total cholesterol, HDL-C and non-hdl cholesterol at 3 and 12 months, then annually, ALT after 3 months and 12 months. 2 Drug Safety Update Aug 2012 vol 6, issue 1: S1

If non-hdl cholesterol reduction < 40%, discuss treatment concordance, lifestyle measures, consider increasing dose of atorvastatin if not maximal. Ensure annual review This is self explanatory and is concordant with the recommendations in the NICE lipid modification guideline. A fasting sample is not required to measure the initial lipid profile. All people presenting with ACS/acute MI should also have a full lipid profile measured on presentation, taking note of the timing of the sample from the onset of symptoms, but this should not delay initiation of treatment. The NICE guideline recommends using non-hdl cholesterol to monitor response, using a percent reduction rather than the same target for all patients. Calculation of a 40% reduction in non-hdl cholesterol for each patient should be included as part of the initial discussion with the patient when agreeing the management plan and treatment with a statin. NICE recommend that all patients, whether treated for primary or secondary prevention, have the response to statins monitored with further review and discussion about concordance and lifestyle behaviours, and possible up titration of atorvastatin dose, when the reduction in non-hdl cholesterol is less than 40%. Past iterations of FATS have not recommended monitoring LFTs on treatment, unless patients are treated with high dose statins or if clinically indicated. However, as more patients are likely to be treated with a high dose statin, and to be compliant with the NICE guideline, measurement of ALT is recommended at 3 and 12 months, at the same time as the lipid profile will be measured, without further monitoring of LFTs thereafter unless clinically indicated. As noted in FATS6, the main purpose of measuring ALT before treatment is to identify people with abnormal results prior to starting drug treatment, but not to exclude them from treatment. Fatty liver is one cause of a raised ALT and is not an indication to exclude people from treatment, and cardiovascular risk modification is an important aspect of their management. Clinicians should refer to the local LFT guideline for further information. In some people with raised liver enzymes a lower dose of statin may be started initially. Members of the FATS group in the past felt that statins were sometimes inappropriately stopped in people who develop abnormal LFTs, and clinical status, repeat blood testing and other causes of abnormal LFTs (refer to the local guideline) should often be considered first before statins are stopped. Routine measurement of CK is not recommended, but should be considered before starting a statin in patients with unexplained muscle pain (although will not be meaningful in patients with an acute MI). If the CK is more than 4 times upper limit of normal 3, the CK should be remeasured after 7 days and if still more than 4 times upper limit of normal, statin treatment should not be started and specialist advice obtained. 3 4 fold increase in CK is used, recognising the current normal levels reported by local biochemistry labs (not 5 fold as included in NICE guidance)

If the CK levels are raised but less than 4 times normal, a statin can be started at a lower dose (see appendix 3). People with symptomatic or prior occlusive vascular disease Drug flow: start Atorvastatin 80 mg od, but: Reconsider choice and or statin dose if there are drug interactions / intolerances / CKD / increased risk of adverse effects see extra notes This is self explanatory. Occlusive vascular disease includes people with coronary heart disease, atheromatous stroke disease and people with peripheral arterial disease. When starting treatment with atorvastatin in patients with established vascular disease, atorvastatin 80 mg od is first line, unless there are concerns about tolerability or interactions. A lower dose of atorvastatin may be considered initially in patients with co-morbidity which increases the risk of adverse side effects or who are taking other drugs that interact with the statin, with a view to titration dependent on response and tolerability. In some cases the maximum dose may also be lower. This may include patients who are older, have a lower body weight and with other conditions such as CKD or conditions which increase the risk of muscle side effects. Previous iterations of FATS have identified the following groups: CKD with egfr 30 ml/min/1.73m 2 Older people particularly those who are frail and or have a low muscle mass Untreated muscle disorder, or other conditions which may be associated with vulnerable muscles eg PMR (CK measurement recommended at baseline in these groups, but not in all people) Untreated hypothyroidism (until corrected) Alcohol abuse The BNF and SPC provide details of potential drug interactions, and some information is also included above. Primary prevention in groups not requiring 10 year cvd risk assessment Type 1 diabetes: all adults ( 18 years) should be considered for statin treatment and in particular, target those with: Microalbuminuria/proteinuria Aged > 40 years Had diabetes for > 10 years Established nephropathy Other cardiovascular risk factors (use clinical judgement) CKD (see NICE / local CKD guideline for diagnosis): offer statin treatment for primary and secondary prevention Drug flow: Atorvastatin 20 mg od (discuss with specialist if egfr < 30 ml/min/1.73m 2 ) if no interactions/intolerances/increased risk of adverse effects, and titrate as appropriate. Familial hypercholesterolaemia: see appendix 2. These recommendations are consistent with those in the NICE lipid modification guideline, and a 10 year cardiovascular risk assessment with a risk assessment tool is not required to inform the decision to offer statin treatment in those with Type 1 diabetes and or CKD (recommendations for making a diagnosis of CKD are available in the associated NICE guideline for chronic kidney disease and from local CKD guidelines). The initial recommended dose of atorvastatin is 20 mg od, unless there are concerns about tolerability or drug interactions (see above) and the NICE lipid

modification guideline recommends discussing with a specialist if the egfr is < 30 ml/min/1.73m 2 ie CKD 4 and 5. Primary prevention in all others (no occlusive vascular disease, Type 1 diabetes, or CKD) Type 2 diabetes Assess 10 year cardiovascular risk using QRISK2 Offer statin treatment if 10 year cardiovascular risk 10% Ensure lifestyle measures are optimised Primary prevention (no diabetes, CKD or occlusive vascular disease) Assess 10 year cardiovascular disease risk using QRISK2 Undertake a full clinical assessment and support lifestyle modification Discuss and agree about statin treatment if 10 year cardiovascular risk 10% and lifestyle modifications are ineffective or inappropriate Additional risk factors Consider additional risk factors when considering drug treatment, together with the QRISK2 risk score, when estimating 10 year CVD risk, notably people: Treated for HIV With severe mental illness Taking medicines that can cause dyslipidaemia (eg antipsychotics, corticosteroids, immunosuppressants) With systemic autoimmune disorders or other systemic inflammatory conditions (eg SLE) With impaired fasting hyperglycaemia Who have made recent changes eg quit smoking, treated BP, lipids etc Drug flow Start Atorvastatin 20 mg od (discuss with specialist if egfr < 30 ml/min/1.73m 2 ), if no interactions/intolerances/increased risk of adverse effects, and titrate as appropriate The recommendations in the updated NICE guideline have led to a substantial revision in FATS7 compared to FATS6. Statins are not now recommended routinely for patients with type 2 diabetes aged over 40 years, but rather that those with Type 2 diabetes have a 10 year cardiovascular risk assessment first. However, those with CKD (those with albuminuria or with egfr <60 ml/min/1.73m 2 with or without albuminuria), should be considered to be at greater risk of cardiovascular disease, and routinely be offered statins (see above). NICE have maintained the recommendation to use a 10 year cardiovascular disease risk assessment, rather than a lifetime risk assessment and have specifically recommended that the QRISK2 tool (available at http://www.qrisk.org/ ) is used in those up to and including 84 years of age. QRISK2 incorporates more risk factors than other tools such as Framingham for example. However, there are some conditions which are not incorporated, including those noted in the summary. These were also recognised in FATS6. An initial assessment of patients being considered for treatment with statins for primary prevention should include as a minimum; Smoking status Alcohol consumption Blood pressure BMI and or other measures of obesity Non-fasting lipid profile ((total cholesterol, HDL cholesterol, non-hdl cholesterol, triglycerides) HbA1c

Renal function and egfr Family history of premature coronary disease Ethnicity Socioeconomic status Secondary causes of dysplipidaemia (see below) A review to ensure there are no symptoms to suggest undiagnosed vascular disease which warrants further investigation. The initial recommended dose of atorvastatin is 20 mg od, unless there are concerns about tolerability or drug interactions (see above). Additional notes (see full supporting notes / appendices): 1. People intolerant of recommended statin see appendix 3 2. Consider FH if TC > 7.5 mmol/l - see appendix 2. Do not use QRISK2. 3. If triglycerides > 4.5 mmol/l: see notes 4. Consider secondary causes of hyperlipidaemia alcohol / thyroid / diabetes / nephrotic syndrome / liver disease / drug induced 5. If ALT raised at baseline, refer to local LFT guidelines. 6. Patients already treated with statins review percent reduction in non-hdl cholesterol from baseline, consider switching to / uptitrating atorvastatin 7. Treatment in general frailty and older people; see supporting notes 1. Previous iterations of FATS have made some recommendations about managing statin intolerance. This has now been further developed to support implementation of FATS7 and is now included as appendix 3. 2. A pathway for assessment of patients with lipid profiles which could be consistent with a familial disorder was developed as an appendix to FATS5 and maintained unchanged for FATS6. This has been updated at the same time as FATS7 has been developed and is included as appendix 2. 3. Serum triglyceride concentrations are affected by the fasting status and if non fasting triglycerides are greater than 4.5 mmol/l a fasting measurement should be considered. All patients with raised triglycerides should be reviewed for secondary causes, including excess alcohol consumption, poor glycaemic control in diabetes and adverse effects of other co-prescribed drugs. If secondary causes are identified, these should be addressed, but if no secondary cause is found or their modification is limited, referral should be made for urgent specialist review if the triglycerides are above 20 mmol/l. In patients with an initial triglyceride concentration between 10 and 20 mmol/l, a repeat fasting measurement should be made after an interval which is more than 5 days, but within 2 weeks together with a review for secondary causes as above. If the fasting measurement remains above 10 mmol/l specialist advice should be obtained. In patients with triglyceride measurements between 4.5 mmol/l and 9.9 mmol/l, cardiovascular risk may be underestimated by the risk assessment tools. Cardiovascular risk factors should be optimised, in particular lifestyle changes. If the non-hdl cholesterol is more than 7.5 mmol/l specialist advice should be obtained. Fibrates, either alone or in combination with a statin, may be appropriate in patients with severe hypertriglyceridaemia at risk of pancreatitis, but are no longer routinely

recommended for cardiovascular disease prevention, including those with Type 2 diabetes. Patients currently treated with fibrates should be reviewed, the impact of additional treatment examined and a decision made whether the benefit of continuing treatment is justified. 4. The recommendation to exclude secondary causes of dyslipidaemia is consistent with previous iterations of FATS and the updated NICE lipid modification guideline. All people with dyslipidaemia being considered for lipid lowering drug treatment should have secondary causes of dyslipidaemia excluded. The table below describes some of the causes of secondary dyslipidaemia. Secondary causes of dyslipidaemias Poor diet, some fad diets and lack of physical activity will have an adverse effect on the lipid profile. Other causes include: Condition / drug treatment Lipid change Cholesterol Triglycerides HDL cholesterol Diabetes mellitus ++/+ - Untreated ++ hypothyroidism Alcohol excess ++/+ + Obesity + - Chronic renal failure + ++ - Nephrotic syndrome ++ + Cholestasis ++ Gout + Pregnancy +/- +/++ Anorexia nervosa + Hypopituitarism +/+++ ++/+ - Long term drug treatment Anticonvulsants +/++ Androgens -/-- Atypical antipsychotics +/+++ +/+++ - Beta blockers + Corticosteroids + + - Ciclosporin + + - HIV/anti-retroviral drugs +/++ Oral oestrogens + + Retinoids ++/+ - 6. The local LFT guideline should be referred to if the ALT is raised. 7. Percent reduction in non-hdl cholesterol from baseline should be assessed wherever possible in patients already treated with statins. Patients treated with an alternative statin, other than atorvastatin, such as simvastatin and a non-hdl cholesterol reduction of less than 40% from baseline, should be considered for switching to atorvastatin, and in those already treated with atorvastatin for up-titration of dose. In all patients concordance with treatment and lifestyle measures should be reviewed and encouraged.

Simvastatin 80 mg od was not recommended in FATS6, due to the increased risk of myopathy. However, there may be some patients still treated with this and if so, these patients should be reviewed and switched to atorvastatin 40 to 80 mg od. In patients maintained on a lower dose of simvastatin, the maximum dose co-prescribed with other agents should be consistent with the recommendations from the MHRA 4, and a summary table of some drugs is included below. Further information about interactions with atorvastatin is included on page 5. All statins are contra-indicated in pregnancy. DRUG INTERACTIONS WITH SIMVASTATIN ASSOCIATED WITH AN INCREASED RISK OF MYOPATHY / RHABDOMYOLYSIS (FROM MHRA 2012) INTERACTING AGENTS PRESCRIBNG RECOMMENDATIONS Itraconazole Ketoconazole Posaconazole Erythromycin Clarithromycin Contra-indicated with simvastatin. Do not coprescribe Telthromycin HIV protease inhibitors eg nelfinavir Nefazodone Ciclosporin Danazol Gemfibrozil Other fibrates (except fenofibrate) Dronedarone Amiodarone Amlodipine Diltiazem Verapamil Fusidic acid Grapefruit juice Do not exceed simvastatin 10 mg daily Do not exceed simvastatin 20 mg daily Patients should be closely monitored. Temporary suspension of simvastatin treatment may be considered. Avoid grapefruit juice when treated with simvastatin. Treatment in older people; see supporting notes This was discussed for FATS4 and has been maintained since with some notable additions. The following was noted during the initial discussion when developing FATS4; Life expectancy in people of different ages (this included all people, not just those who are well) was reviewed. At the age of 80 years, the average life expectancy in men is about 7 years and in women 9 years. At the age of 90 years, the average life expectancy in both men and women is about 4 years People who are older are more likely to have a circulatory death than those who are younger. If statins are of benefit, that benefit may be greater in an older person than a younger Correcting for frailty, co-morbidity and first year events, cholesterol is a risk factor in older people The statin trials show no trend suggesting a difference in efficacy of statin treatment with older age 4 Drug Safety Update Aug 2012 vol 6, issue 1: S1

The updated NICE lipid modification guideline has recommended the use of QRISK2 to estimate 10 year cardiovascular disease risk in those aged up to and including the age of 84 years. The NICE guideline has further recommended that people aged 85 years and older are at increased risk of cardiovascular disease because of age alone, particularly people who smoke or have raised blood pressure, and that atorvastatin 20 mg od may be of benefit in reducing the risk of non-fatal MI. Members of the FATS group expressed concern about the potential for indiscriminate prescribing of statins in older people, in particular the use of high dose statins, given the increased risk of adverse effects in older people, and the lack of evidence showing reduced mortality in the very elderly. However, equally of concern is that older people may be denied access to treatment, purely on the basis of their age, and older patients should be assessed for the likely benefit based on such factors as life expectancy, underlying conditions increasing cardiovascular risk and individual patient preferences as well as factors which increase the risk of adverse effects, including general frailty, co-morbities and polypharmacy. When statins are prescribed, a lower dose than that recommended routinely may be appropriate.

APPENDICES Appendix 1 Examples of statin / ezetimibe costs - 28 days (December 2014) Simvastatin 10 mg od 0.90 Simvastatin 20 mg od 0.98 Simvastatin 40 mg od 1.23 Atorvastatin 10 mg od 1.19 Atorvastatin 20 mg od 1.45 Atorvastatin chewable 20 mg od (30) 26.40 Atorvastatin 40 mg od 1.67 Atorvastatin 80 mg od 2.68 Pravastatin 40 mg od 2.00 Rosuvastatin 5 mg od 18.03 Rosuvastatin 10 mg od 18.03 Rosuvastatin 20 mg od 26.02 Rosuvastatin 40 mg od 29.69 Ezetimibe 10 mg od 26.31

Appendix 2 People with possible or definite familial hypercholesterolaemia (FH); supplementary guidance to FATS To be read in conjunction with current iteration of FATS FATS Steering Group December 2014

Background and definition of Familial Hypercholesterolaemia (FH) It is estimated that about 4% of the primary care population will have hypercholesterolaemia with total cholesterol > 7.5 mmol/l and or LDL cholesterol > 4.9 mmol/l. About 1 in 20 of these will have FH. FH is a condition which shows an autosomal dominant pattern of inheritance within families (half of first degree and a quarter of second degree relatives will also be affected) and is associated with a very high risk of premature coronary heart disease if left untreated (>20% of males before 40 years, 50% by 50 years; 50% of females by age 60 years). The concentration of LDL cholesterol is doubled from birth in those affected, but primary prevention with lifestyle changes and statin treatment (to reduce LDL-C by >50%) is effective in reducing mortality to population levels or below. The estimated prevalence of FH in the UK population is 1 in 500 or a total of 6000 in the North East, of whom it is estimated that currently less than 1000 have been identified and treated. The Simon Broome criteria are used for a clinical diagnosis of familial hypercholesterolaemia (FH). That is in adults; Definite FH Total cholesterol > 7.5 mmol/l (either pre-treatment or highest on treatment) in adults over 16 years, or LDL cholesterol > 4.9 mmol/l plus Either tendon xanthomata in the person or 1 st or 2 nd degree relative and/or DNAbased evidence of an LDL receptor mutation or familial defective apob-100. Possible FH Total cholesterol > 7.5 mmol/l (either pre-treatment or highest on treatment) in adults over 16 years, or LDL cholesterol > 4.9 mmol/l plus one of the following Family history of myocardial infarction before age 50 years in 2 nd degree relative or before 60 years in 1 st degree relative Family history of raised total cholesterol > 7.5 mmol/l in 1 st or 2 nd degree relative. Non-HDL cholesterol thresholds are also included and is a valid measure from non fasting samples. Diagnosis and management of people with total cholesterol greater than 7.5 mmol/l and or LDL cholesterol > 4.9 mmol/l, and or non HDL cholesterol > 5.9 mmol/l Introduction This is additional guidance developed to supplement FATS. It specifically makes recommendations for the assessment and management of all people with a total cholesterol > 7.5 mmol/l and or a LDL cholesterol > 4.9 mmol/l, and or non HDL cholesterol > 5.9 mmol/l. FATS already recognises that such people should be further assessed for a diagnosis of Familial Hypercholesterolaemia (FH). The current document also includes guidance about how people with possible or definite FH can be identified and distinguished from others with a high cholesterol to facilitate targeted family cascade screening taking into account the recommendations in the

NICE clinical guideline 71, Identification and management of familial hypercholesterolaemia 5. The flow chart below outlines the steps to take when a total cholesterol > 7.5 mmol/l and or LDL cholesterol > 4.9 mmol/l and or non-hdl cholesterol > 5.9 mmol/l is found and identifies which patients should be referred to the lipid clinic. A referral form to refer a patient with possible familial hypercholeterolaemia or other suspected familial lipid disorder to the lipid clinic is included below. Patients referred for other reasons, such drug intolerance, should be referred by written letter. This guidance is intended for all clinicians in the Newcastle, North Tyneside, Northumberland areas involved in treating people for primary and secondary prevention of cardiovascular disease, and should be used in conjunction with the current iteration of FATS. 5 available at http://guidance.nice.org.uk/cg71

Flow chart for the assessment of severe hypercholesterolaemia Patient with total cholesterol > 7.5 mmolo/l and or LDL cholesterol > 4.9 mmol/l Total cholesterol > 7.5 mmol/l and or LDL cholesterol (fasting) > 4.9 mmol/l and or non HDL cholesterol > 5.9 mmol/l Take fasting blood for Repeat lipid profile AND Are there any secondary causes (see table in current iteration of FATS) Blood and urine samples (request Secondary causes of hyperlipidamia laboratory profile ) Assess Current drug treatment Lifestyle including diet (including any fad diets ) and physical activity Alcohol history Glycaemic control if diabetes Notes 1. Personal history or first degree relative with confirmed CHD (MI, CABG, PCI and or definite coronary artery disease on coronary angiography) < 60 years or second degree relative with confirmed CHD < 50 years, and or reliable family history of total cholesterol > 7.5 mmol/l 2. If fasting triglycerides > 4.5 mmol/l, but 10 mmol/l consider discussion with local advisor. Refer to current iteration of FATS 3. All patients should have lifestyle advice offered and an overall management plan discussed and agreed. 4. Refer to current iteration of FATS / BNF / SPC for contra-indications, interactions and increased risk of adverse events with atorvastatin 20 mg od Are there any secondary causes (refer to table in notes)? Yes No Manage any secondary causes and reassess Is repeat LDL-C > 4.9 mmol/l and or non HDL-C > 5.9 mmol/l? Yes No Are tendon xanthomata (visible and or palpable) present and or Is there a personal and or family history of confirmed premature CHD / raised cholesterol Assess and manage 10 year cvd risk (refer to current iteration of FATS) Consider atorvastatin 20 mg od Yes Refer to lipid clinic Is: No Total cholesterol > 9 mmol/l, or Non HDL cholesterol > 7.5 mmol/l, or LDL cholesterol > 6.5 mmol/l, and or Fasting triglycerides > 10 mmol/l? Yes Refer to lipid clinic No Consider discussing and treating with atorvastatin 20 mg od (refer to current iteration of FATS) If there is clinical concern, uncertain family history, poor response to optimal statin (ie < 40% reduction in non HDL cholesterol), younger patients, refer to lipid clinic

Secondary causes of dyslipidaemias Some of these are summarised in the current iteration of FATS. People with occlusive vascular disease The above flow chart should be adopted for all people presenting with a total cholesterol > 7.5 mmol/l or LDL cholesterol (measured from a fasting sample) > 4.9 mmol/l, but the following was noted. People with coronary heart disease People with a personal history of confirmed coronary heart disease may not have the results of the initial lipid profile confirmed before treatment with a statin is started. These patients should still have secondary causes excluded (as above) and should be considered for referral to the lipid clinic if they have; a total cholesterol > 7.5 mmol/l, LDL cholesterol (fasting) > 4.9 mmol/l, non-hdl cholesterol > 5.9 mmol/l AND a personal history of confirmed CHD age < 60 years, and or tendon xanthomata, and or a family history which meets the Simon Broome criteria (see above) People with stroke disease and PAD People with a personal history of stroke and PAD should be managed as recommended in the flow chart, although a fasting lipid profile may not always be taken before a statin is started, particularly in those with an acute presentation. Lipid clinic The lipid clinic will; Confirm a clinical diagnosis of FH or alternative diagnosis and recommend coding in primary care EMIS code for familial hypercholesterolaemia C3200 SYSTMONE code C3200 Provide lifestyle and dietetic advice Start and/or titrate lipid lowering drug treatment. Intensive statin treatment will be offered to people with FH, aiming to lower LDL cholesterol (or non-hdl cholesterol) by 50% or more. A non generic statin (rosuvastatin) and combination therapies may be needed, although these should only be used following recommendation from specialist care. Provide information, including about CHD risk and in women of child bearing age, the importance of avoiding statins for 3 months before conception and throughout pregnancy. Identify and arrange investigation if there are any symptoms or signs of cardiovascular disease Use the Dutch Lipid Clinics Network score to determine the likelihood of familial hypercholesterolaemia and prioritise those with a score 6 for genetic testing. Recommend if family cascade screening is appropriate, using measurement of lipid profiles in other family members (see below) Arrange follow up and an annual structured review (see below) Follow up and annual review All people with FH require an annual structured review. This may be done in the lipid clinic or in primary care dependent on clinical need, and as a minimum includes;

Fasting lipid profile; comparison to previous level of LDL cholesterol and review of LDL lowering from baseline Current drug treatment, concordance and any problems with side effects Lifestyle and dietetic review and advice Identify any symptoms or signs of cardiovascular disease or new cardiovascular event, and arrange appropriate investigation Update any family history of CHD events and progress with cascade screening. Family cascade screening for Familial Hypercholesterolaemia Genotyping is being introduced in the North East for patients most likely to have a familial hypercholesterolaemia, following assessment in the lipid clinic. The lipid clinics will use the Dutch Lipid Clinics Network score. Patients with a score 6 are anticipated to have an estimated pick up rate of a positive genotyping of approximately 40% or more, whilst those with a score 10 a pick up of more than 80%. Patients being considered for genotyping will be seen by a specialist nurse who will complete a family history with them and arrange appropriate further testing. The Dutch Lipid Clinics Network Score is calculated from the table below and is used in the lipid clinic, but should not be used to decide if a patient should be referred to the lipid clinic. Patients who do not fulfil the criteria for genotyping, but in whom cascade family screening is recommended, will have this explained in the lipid clinic and if they wish will be given information and a letter which their first degree relatives can take to their own GPs to have a lipid profile measured. The results of the fasting lipid profile in family members should be interpreted using the tables for first degree relatives in the NICE clinical guideline 71, Identification and management of familial hypercholesterolaemia. Pages 43 to 45 of the NICE guideline are pasted below. Family members who fall into the red zone or grey zone should be considered for referral to the lipid clinic. Those in the red zone are very likely to have familial hypercholesterolaemia and those in grey zone require further specialist assessment for diagnosis.

Tables for interpretation of lipid profiles if used in family cascade testing NICE clinical guideline 71, Identification and management of familial hypercholesterolaemia. Pages 43 to 45, available at http://guidance.nice.org.uk/cg71

REFERRAL OF ADULTS ( 16 yrs) WITH POSSIBLE FAMILIAL HYPERCHOLESTEROLAEMIA (FH) or OTHER FAMILIAL HYPERLIPIDAEMIA TO THE LIPID CLINIC This form can be used to refer adults with possible/definite FH or possible FH to the lipid clinic. The local guidelines for patients with possible or definite FH provide more information. Date of Referral; Referring G.P: Address:...... Post Code: Telephone No:.. Fax No:.. Patient s Surname:... Previous Surname (if married): Forename(s):. Address:... Postcode:... Telephone No. Daytime:.. Special Needs: (e.g. hearing loss, physical disability) D.O.B. Evening:.. Age: Interpreter Required: Yes No Language:. NHS No:. Hospital ID No if available: BIOCHEMICAL RESULTS TO ACCOMPANY THE REFERRAL Lipid profiles (at least one fasting), preferably including highest pre-treatment results. Date Total chol. HDL-C. Trigs. LDL-C (fasting). Date Total chol. HDL-C. Trigs. LDL-C (fasting). Date Fasting glucose. Date HbA1C Date TSH. Date LFT Albumin Bilirubin Alk phos ALT Date Urine protein quantification (PCR or ACR (ring one)). CLINICAL INFORMATION and DRUG HISTORY Is this the first degree relative of a confirmed familial hypercholesterolaemia case? Yes No Is there a personal history of coronary disease < 60 years? Yes No Are there first degree relatives with proven coronary disease < 60 years? Yes No Are there second degree relatives with proven coronary disease < 50 years? Yes No Is there a personal history of other premature CVD < 60 years? Yes No Is there a family history of other premature CVD < 60 years? Yes No Is there a family history of cholesterol > 7.5 mmol/l? Yes No Are tendon xanthomata present? Yes No Alcohol consumption (units per week) List any recent drugs which may cause hyperlipidaemia (attach list of all current drugs) Please send completed forms with a copy of the patient s current drug history and details of any other relevant history to the Lipid Clinic Dr D Neely, Lipid Clinic, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust Dr P McKenna, Lipid Clinic North Tyneside Hospital, Northumbria Healthcare NHS Foundation Trust

Appendix 3 Additional guidance for assessment and management of statin intolerance Statin intolerance definition Intolerance to initial statin therapy is defined as the presence of clinically significant adverse effects from statin therapy that are considered to represent an unacceptable risk to the patient or that may result in compliance with therapy being compromised. Adverse effects include evidence of new-onset muscle pain (which may be associated with increased serum levels of the muscle enzyme CK, indicating of muscle damage), increased levels of liver function enzymes, significant gastrointestinal disturbances. Musculoskeletal are the most frequently reported adverse effects, however more severe forms of muscle toxicity are infrequent (see Table SRM Classification, page 29) and almost always avoidable if simple precautions are observed. Recommendations for the assessment and management of adverse muscle side effects in patients being considered for, or treated with statins, were developed as a consensus by the FATS group. These are presented as a flow chart and notes, which should be read together. 24

Flowchart for Assessment of Suspected Statin Related Myopathy Notes New onset muscle pain 1. Before treatment check baseline thyroid, liver and renal function and consider baseline CK in at risk groups 2. Avoid high doses, highly lipophilic statins (eg simvastatin, atorvastatin) in at risk groups e.g. elderly, frail, renal or liver dysfunction, pre-existing musculoskeletal disease, alcohol abuse Consider other causes? NO Are the symptoms typical for statin related myopathy?* 3. Consider any potential drug interactions, including grapefruit juice 4. Warn patients about side effects, specifically muscle symptoms 5. *Typical symptoms of statin related myopathy are symmetrical pain or weakness in large proximal muscle groups, worsened by exercise and onset within 3-6 months of statin initiation. Measure CK, assess symptom severity +/- repeat baseline assessment** 6.** If new onset muscle pain of >2 weeks duration in a patient previously statin tolerant for >6 months, recheck thyroid, liver and renal function, consider any potential drug interactions (including grapefruit juice) to identify correctable risk factors CK < 4 fold normal, and or Symptoms tolerable Quickly correctable risk factor** No clinical concern CK > 4 fold normal, and or Symptoms Intolerable / clinical concern No quickly correctable risk factor** Improvement within 2 weeks Resolved within 6 weeks Patient happy to continue NO Stop statin for 4 6 weeks Document time to onset, duration to resolution Consider other causes? e.g. PMR, Vitamin D Deficiency Check Bone profile, VitD, CRP NO Have the symptoms resolved? Has CK normalised? Wait 2 weeks NO Has the patient been symptom free >2 weeks? Review lipid profile, cardiovascular risk and treatment goals Recommence current or alternative statin at lowest dose Consider a less lipophilic statin if intolerant to a lipophilic drug No recurrence of symptoms Titrate at 8 week intervals with review of lipid response (percent reduction in non HDL cholesterol see FATS) Recurrence of muscle symptoms Symptoms Intolerable Short time to onset Symptoms tolerable Treatment goals achieved Patient happy to continue NO Stop Statin and consider further options 25

Notes for advice and monitoring for adverse effects (see flow chart) 1. Before offering a statin, ask the person if they have had persistent generalised unexplained muscle pain, whether associated or not with previous lipidlowering therapy. If they have, measure creatine kinase levels (CK). If creatine kinase levels are more than 4 times the upper limit of normal, re-measure creatine kinase after 7 days. If creatine kinase levels are still 4 times the upper limit of normal, do not start statin treatment. If creatine kinase levels are raised but less than 4 times the upper limit of normal, start statin treatment at a lower dose. Unless free of symptoms of muscle pain re-measure creatinine kinase in 6 weeks. 2. Before prescribing a statin, check baseline thyroid, liver and renal function and consider any potential drug interactions and avoid the highest doses in at risk groups such as elderly, female, those with musculoskeletal disease, renal or liver dysfunction. 3. Warn patients about adverse effects, specifically muscle symptoms. Advise people who are being treated with a statin to seek medical advice if they develop muscle symptoms (pain, tenderness or weakness). If this occurs, measure creatine kinase (CK) If CK levels are raised more than 4 times the upper limit of normal, stop statin treatment immediately. The dose of statin used, time to onset and the anatomical distrbution of symptoms should be documented 4. If people report muscle pain or weakness while taking a statin, explore other possible causes of muscle pain or weakness (with or without raised CK) particularly if the symptoms are not typical of statin related muscle toxicity, or if they have previously tolerated statin therapy for more than 3 months. 5. If someone reports adverse effects when taking high-intensity statins discuss the following possible strategies with them: a. stopping the statin and trying again when the symptoms have resolved to check if the symptoms are related to the statin b. reducing the dose within the same intensity group c. changing the statin to a lower intensity group. In all cases, the recommendations in the event of muscle side effects should be followed (see above) 6. If a person is not able to tolerate a high-intensity statin aim to treat with the maximum tolerated dose. Tell the person that any statin at any dose reduces cardiovascular disease risk. 7. Seek specialist advice about options for treating people at high risk of cardiovascular disease who are intolerant (SRM 2 or above) to 3 different statins or who develop myopathy (SRM 3-6) 26

Treatment options for people at high cardiovascular risk who are intolerant to 3 different statins: 1. Low dose, non-daily long acting statin (atorvastatin 10 mg or rosuvastatin 5mg one to three days per week) 2. Ezetimibe, coadministered with maximum tolerated generic statin therapy, when dose titration is limited by intolerance to statin therapy (as defined above) 3. Ezetimibe monotherapy is an option for those who are intolerant to low dose, non-daily statin therapy (as defined above). 4. Lipoprotein apheresis should be considered as a last resort in patients with Familial Hypercholesterolaemia and LDL-Cholesterol greater than 5 mmol/l despite maximum tolerated statin therapy or in in people with progressive vascular disease who are intolerant of statin therapy. These patients should be assessed in a specialist lipid clinic. The table describes average percent reduction in LDL cholesterol with different statins/doses (taken daily). Similar reductions in non-hdl cholesterol can be assumed. Reduction in LDL cholesterol Dose (mg/day) 5 10 20 40 80 Fluvastatin 21% 27% 33% Pravastatin 20% 24% 29% Simvastatin 27% 32% 37% 42% * Atorvastatin 37% 43% 49% 55% Rosuvastatin 38% 43% 48% 53% 20% 30%: low intensity 31% 40%: medium intensity Above 40%: high intensity 27

Statin related myotoxicity (SRM) classification Table. Statin Related Myotoxicity (SRM) Classification Phenotype Incidence Definition SRM 0 CK elevation <4XULN 1.5-26% No muscle symptoms SRM 1 Myalgia, tolerable 190/100,000 patient years; 0.3 to 33% Muscle symptoms without CK elevation SRM 2 Myalgia, intolerable 0.5% Muscle symptoms, CK <4xULN, complete resolution on dechallenge SRM 3 Myopathy 5/100,000 patient years CK elevation >4xULN <10xULN ± muscle symptoms, complete resolution on dechallenge SRM 4 Severe myopathy 0.11% CK elevation >10 x ULN<50x ULN ± muscle symptoms complete resolution on dechallenge SRM 5 Rhabdomyolysis 0.1-8.4/100,000 patient years CK elevation >10xULN with evidence of renal impairment + muscle symptoms or CK>50x ULN SRM 6 Autoimmune- ~2/million per year HMGCR antibodies, mediated necrotising myositis HMGCR expression in muscle biopsy incomplete resolution on dechallenge 28

Appendix 4 Membership of the FATS steering group Dr Jane Skinner, Consultant Community Cardiologist, Newcastle upon Tyne Hospitals NHS Foundation Trust (guideline co-ordinator) Anne-Marie Bailey, Pharmaceutical Advisor, NHS North of England Commissioning Support Unit Dr Stuart Bennett, Consultant in Diabetes, Northumbria Healthcare NHS Foundation Trust Dr John Bourke, Consultant Cardiologist, Newcastle upon Tyne Hospitals NHS Foundation Trust Dr Andrew Chalmers, GP, Beaumont Park, Whitley Bay Rebecca Coon (Samantha Wood from December 2014), Pharmacist, Northumbria Healthcare NHS Foundation Trust Dr Helen Coundon, GP and prescribing lead, North Tyneside CCG Dr Richard Curless, Northumbria Healthcare Trust Dr Anand Dixit, Consultant in Stroke Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust Dr J Colin Doig, Consultant Cardiologist, Northumbria Healthcare NHS Foundation Trust Dr A Gall, GP and prescribing lead, Newcastle North and East CCG Dr Sharon Gandy, GP, North Shields Dr Akif Gani, Consultant in Elderly Care, Newcastle upon Tyne Hospitals NHS Foundation Trust Dr Ifti Haq, Consultant Cardiologist, Newcastle upon Tyne Hospitals NHS Foundation Trust Dr Suren Kanagasundaram, Consultant in Renal Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust Dr N Leech, Consultant Diabetologist, Newcastle upon Tyne Hospitals NHS Foundation Trust Dr Nick Lewis-Barned, Consultant in Diabetes, Northumbria Healthcare NHS Foundation Trust Matthew Lowery, Formulary Pharmacist, Newcastle upon Tyne Hospitals NHS Foundation Trust Dr Paul McKenna, Consultant Chemical Pathologist, Northumbria Healthcare NHS Foundation Trust Dr Frances Naylor, GP and LTC lead, Northumberland CCG Dr Dermot Neely, Consultant in Clinical Biochemistry and Metabolic Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust Dr Wan-Fai Ng, Consultant Rheumatologist, Newcastle upon Tyne Hospitals NHS Foundation Trust Dr Craig Runnett, Consultant Cardiologist, Northumbria Healthcare NHS Foundation Trust Dr Mike Scott, GP, Newburn Surgery, Newcastle Dr Caroline Sprake, GP and LTC lead, North Tyneside CCG Prof Gerry Stansby, Consultant Vascular Surgeon, Newcastle upon Tyne Hospitals NHS Foundation Trust Deb Stone, Dietician, Healthy Hearts, Northumbria Healthcare NHS Foundation Trust Claire Thomas, Medicines Management Lead, Northumberland Tyne and Wear NHS Trust 29